Molecular profiling of ctDNA from NCI-MATCH patients enrolled for treatment with mTOR1/2 inhibitor sapanisertib (arm M) and the Hedgehog pathway inhibitor vismodegib (arm T).
Authors: Jennifer S. LoCoco, Biswajit Das, Sorena Rahmanian, Ting-Chia Chang, Jennifer Silhavy, Li Chen, Robin Harrington, Amanda Peach, Yao Fu, Lisa McShane, Jessica Li, Alice P. Chen, Naoko Takebe, Lyndsay Harris, David R. Patton, Traci L. Pawlowski, Phillip G. Febbo, James H. Doroshow, P. Mickey Williams, Chris Alan Karlovich
Journal: Journal of Clinical Oncology (2023)

3047 Background: The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) multi-arm phase II clinical trial tested biopsies from patients with advanced refractory cancer to assign treatment based on tumor molecular profile. Enrollment criteria for treatment with the mTOR1/2 inhibitor sapanisertib in Arm M, or the Hedgehog pathway inhibitor vismodegib in Arm T, included detection of mutations in TSC1/TSC2 or PTCH1/SMO in tissue, respectively. For a subset of patients enrolled on these two arms, matched plasma was also collected at time of enrollment or on treatment to evaluate ctDNA. Methods: Screening for NCI-MATCH was based on tissue sequencing that was initially performed centrally using the 143-gene Oncomine Comprehensive Assay version 2 (OCAv2) and later referred to NCI-MATCH Designated Laboratory (DL) Network to perform sequencing for patient referral. Cell-free DNA (cfDNA) extracted from plasma collected in Streck tubes was input at 10 – 30 ng into a modified version of the Illumina TruSight Oncology 500 assay (TSO 500). Following error correction and read collapsing post-sequencing, variant calls were made and concordance between cfDNA libraries meeting prespecified QC criteria and tissue was evaluated. Results: Plasma, representing multiple collection timepoints, was available for 30/49 Arm M and 21/34 Arm T enrolled patients. A total of 95 cfDNA libraries, including replicates, were constructed and sequenced. Unique patient samples were tested across various timepoints (n = 35 pretreatment; n = 35 Cycle 2 Day 1; n = 8 at progression) plus replicates, with 90 (94.7%) libraries passing all prespecified QC criteria. Among Arm M patients there were 3 patients whose enrollment variant did not overlap with the TSO 500 gene panel. In total, 14 of 27 (51.8%) patients in Arm M and 18 of 21 (85.7%) patients in Arm T were concordant for enrollment mutation for at least one collection timepoint. In Arm T, 85.7% (n=38) of patient samples had at least one oncogenic or likely oncogenic (O/LO) mutation in the tumor sample at enrollment, with 73.6% (n = 28) of those also being detected by cfDNA. Interestingly, within Arm M and Arm T, a total of 7 patient samples were detected as MSI-H, with corresponding bTMB scores ranging from ~6 to &gt; 100 Mut/Mb (median = 86.7). Conclusions: Detection of the enrollment mutations in treatment arms was observed in 51.8% - 85.7% of patients tested by ctDNA with overall variant concordance between tissue and ctDNA of at least 73.6%. These findings support the use of liquid biopsy as a tool for understanding genomic profiles of cancer patients both at diagnosis and progression, less invasively than standard tissue biopsies. In addition, 7 patients were identified as MSI-H, suggesting that blood-based testing could complement tissue testing for identifying patients who may benefit from targeted therapy.